| 1. |
- Cataldo, Luis Rodrigo, et al.
(författare)
-
The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells
- 2021
-
Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 1532-8600.
-
Tidskriftsartikel (refereegranskat)abstract
- The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS amplification. PPP1R1A silencing in β-cell lines impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical β-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the β-cell transcription factor MafA is required for PPP1R1A expression and that reduced β-cell PPP1R1A levels impaired β-cell function and contributed to β-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic β-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments.
|
|
| 2. |
- Stamenkovic, Jelena, et al.
(författare)
-
Regulation of core clock genes in human islets.
- 2012
-
Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 61:7, s. 978-985
-
Tidskriftsartikel (refereegranskat)abstract
- Nearly all mammalian cells express a set of genes known as clock genes. These regulate the circadian rhythm of cellular processes by means of negative and positive autoregulatory feedback loops of transcription and translation. Recent genomewide association studies have demonstrated an association between a polymorphism near the circadian clock gene CRY2 and elevated fasting glucose. To determine whether clock genes could play a pathogenetic role in the disease, we examined messenger RNA (mRNA) expression of core clock genes in human islets from donors with or without type 2 diabetes mellitus. Microarray and quantitative real-time polymerase chain reaction analyses were used to assess expression of the core clock genes CLOCK, BMAL-1, PER1 to 3, and CRY1 and 2 in human islets. Insulin secretion and insulin content in human islets were measured by radioimmunoassay. The mRNA levels of PER2, PER3, and CRY2 were significantly lower in islets from donors with type 2 diabetes mellitus. To investigate the functional relevance of these clock genes, we correlated their expression to insulin content and glycated hemoglobin levels: mRNA levels of PER2 (ρ = 0.33, P = .012), PER3 (ρ = 0.30, P = .023), and CRY2 (ρ = 0.37, P = .0047) correlated positively with insulin content. Of these genes, expression of PER3 and CRY2 correlated negatively with glycated hemoglobin levels (ρ = -0.44, P = .0012; ρ = -0.28, P = .042). Furthermore, in an in vitro model mimicking pathogenetic conditions, the PER3 mRNA level was reduced in human islets exposed to 16.7 mmol/L glucose per 1 mmol/L palmitate for 48 hours (P = .003). Core clock genes are regulated in human islets. The data suggest that perturbations of circadian clock components may contribute to islet pathophysiology in human type 2 diabetes mellitus.
|
|
